1. Field of the Invention
This invention relates generally to the delivery of ions to ion detection devices. More specifically, the invention describes a method and apparatus for improving the ability to focus ions after they are formed by using a front-end device so that a greater number of ions can be directed to an ion detection device for detection or further analysis.
2. Description of Related Art
The prior art is replete with improvements in systems that enable the formation of ions, and in the detection and analysis thereof. However, one of the difficulties of performing ion detection and analysis is the task of delivering a large quantity of ions to an ion detection or analysis device. The ions are difficult to direct to an appropriate orifice of an ion detection device for various reasons that are known to those skilled in the art. Nevertheless, the more ions that can be delivered to the ion detection device, the more “sensitive” or accurate the results will be. Such devices include an electron multiplier, Faraday plate, ion mobility spectrometer, and a time-of-flight mass spectrometer. In general, the present invention should be considered to apply to any device that needs to perform ion detection and/or analysis, whatever that device might be. But all of these devices should be considered to fall within the single descriptive term of “ion detection device”.
An important technique referred to as “electrospray ionization” was developed in order to improve the process of delivering ions to an ion detection device. For example, in electrospray ionization, a liquid sample is directed through a free end of a capillary tube or orifice, wherein the tube is coupled to a high voltage source. In general, the free end of the capillary or electrospray sprayer tip is spaced apart from an orifice plate or capillary that has a sampling orifice that leads to a vacuum chamber of the ion detection device. The orifice plate is also coupled to the high voltage source. The electric field generates a spray of charged droplets, and the droplets evaporate to produce ions.
Electrospray ionization has grown to be one of the most commonly used ionization techniques for mass spectrometry, and efforts continue to improve its performance. Typically, the electrospray tip must be very close to the orifice of the ion detection device in order to maximize the conduction of ions from the electrospray tip into the ion detection device. However, due to space-charge repulsion, most ions never reach the sampling orifice.
Nevertheless, the significance of electrospray ionization for mass spectrometry has recently been emphasized by the rewarding of the Nobel Prize for work in this area. Electrospray ionization is most recognized today for its application to biomolecules where high “sensitivity is of paramount importance.” It should be remembered that throughout this document, sensitivity more accurately refers to the total number of ions that can be delivered to an ion detection device. Electrospray ionization is known for its high sensitivity; however, the present invention will demonstrate that this process has the potential of becoming even more sensitive.
It is now known that a major limitation in sensitivity when using electrospray ionization and with ion detection devices is due to low ion transmission from the electrospray ionization source through the atmosphere-to-vacuum sampling orifice into an inner chamber of an ion detection device such as a mass spectrometer. Although the ionization efficiency approaches 100%, the typical ion transmission efficiency from the electrospray ionization source to the extraction region of the ion detection device is only 0.01-0.1%.
When dealing with ion detection devices, it is important to look closely at the process of ion delivery. During the process of electrospray ionization, analyte ions are generated at atmospheric pressure and transferred into a low-pressure extraction region of the mass spectrometer via a conductance-limiting aperture located in a high pressure region. Gas-phase collisions and Coulombic repulsion that are inevitably involved result in expansion of the ion cloud, directing ions away from the extraction region of the mass spectrometer, thus decreasing the sensitivity. Although conventional ion optic devices based on Coulombic effects can effectively focus ions in vacuum, they are largely ineffective in avoiding or reversing ion-cloud expansion generated by gas-phase collisions and Coulombic repulsion at high pressures.
To assist in desolvation and transmission of ions from the electrospray sprayer tip to the sampling capillary inlet, Henion et al. taught an “ion spray” device in which a high velocity sheath flow nebulizing gas was directed past the electrospray sprayer tip. By optimizing the flow rate for focusing and desolvating the electrosprayed ions, an approximately 30% increase in ion signal intensity was obtained as compared to a relatively low flow rate. However, no indication was given as to ion signal improvement compared to a conventional electrospray ionization source without the nebulizer-assisted device.
The prior art as taught by Covey et al. teaches that an electrospray ionization source in which a heated gas flow was directed at an angle toward the flow axis of a nebulizer-assisted electrospray source, and intersected the droplet flow at a region upstream of the sampling orifice of the mass spectrometer. The intersecting gas flows mixed with the droplet flow in a turbulent fashion, and helped to desolvate ions in the droplets and move them toward the sampling orifice. The intersecting flow device reportedly provided an increase in sensitivity of over 10 times, and significantly lowered the background in the resulting mass spectra. However, it was necessary to carefully control the two flows and the angle between them for stability of the electrospray. Thus, better performance may be difficult to obtain and maintain.
The prior art as taught by Smith et al. has improved the sensitivity of electrospray ionization by designing a so-called “ion funnel” in the first vacuum stage of the mass spectrometer between the sampling capillary inlet, and a skimmer that is internal to a mass spectrometer. This ion funnel consists of a series of cylindrical ring electrodes of progressively smaller internal diameters. By co-applying radio frequency (RF) and direct current (DC) electric fields on the electrode series, the ion cloud is more effectively focused and the Coulombic-driven ion cloud expansion is reduced under pressures of 10−4 up to 9 Torr. Thus, ions are more efficiently captured, focused and transmitted as a collimated ion beam from the sampling orifice to the skimmer. Over an order of magnitude increase in ion signal intensity was reported as compared to a conventional electrospray ionization source.
A recent improvement to this ion funnel is the use of a multi-capillary inlet. With the combination of multi-capillary inlet and ion funnel, Kim et al. reported ion transmission efficiencies that are 23 times greater than can be obtained with conventional electrospray ionization ion optics. However, the ion funnel improves ion transport only at reduced pressures and cannot be applied at atmospheric pressure conditions between the electrospray tip and sampling nozzle where most ion losses occur.
Until now, few users have reported effective methods of improving ion signals in the high pressure region between the sprayer and the sampling orifice of the mass spectrometer. One group of users placed a ring electrode downstream from an electrospray ionization sprayer to focus ions into the mass spectrometer. Another group of users employed a focusing ring at atmospheric pressure on the inner wall of a heated glass capillary interface for electrospray ionization. Still other groups reported similar designs of a heated silica capillary to assist in desolvation in which end plate and cylindrical lenses were mentioned. These lenses were located at substantial distances from both the sprayer and the inlet orifice of the heated capillary. According to these users, the electrode rings were useful; however, no mention was made concerning how much they improved ion signal intensities. Finally, another group of users described the use of an oblong-shaped stainless steel electrode ring that was connected to a high voltage power supply, and placed near the electrospray tip at a potential less than that of the sprayer. It was reported that this lens produced a 2-fold increase in ion signal intensity and a 2-fold reduction in the signal relative standard deviation (RSD). Other advances included an increase in formation of multiple charged ions, less critical positioning of the sprayer for optimum performance, and more ease in use compared to the ion funnel and intersecting flow devices.
An alternative to focusing the electrospray ion beam toward the sampling orifice is to place the electrospray tip as close to the sampling nozzle as possible so that a larger portion of the spray enters the vacuum region. Low flow rates from small-bore electrospray ionization tips are desirable for stability of the “Taylor cone” and production of fine electrospray droplets. This combination has been accomplished using microspray and, especially, nanospray sources. The improvement in response can be explained by the fact that sprayed droplets are already small enough to produce gas-phase ions directly. Analyte concentrations down to low picomolar can be easily sprayed without sheath flow or pneumatic assistance for mass spectrometer detection.
For this reason, microspray and nanospray sources can be operated with the electrospray tip very close to the sampling orifice of the mass spectrometer. However, the closeness is limited by the electrical discharge threshold between the high voltage sprayer and the nozzle counter electrode, which is dependent on the voltage applied to the electrospray ionization sprayer tip. In order to overcome these limitations, different groups of users reported low-pressure electrospray devices, in which analyte solutions were electrosprayed inside the vacuum chamber at reduced pressures. Unfortunately, incomplete desolvation largely offset any improvement in increased sample introduction. Moreover, when the electrospray device was positioned in a very-low-pressure region, one group of users reported significant loss of analytes and fine droplets on the walls of the vacuum chamber and heated transfer line, thus, seriously decreasing the sensitivity.
It is generally believed that electrospray ionization technology has reached the point where modifications produce only minor gains in ion transmission in atmospheric pressure regions of electrospray ionization sources. Accordingly, what is needed are new approaches that will take advantage of the high sensitivity that is potentially available but not yet exploited by state of the art techniques in ion delivery.